This application proposes a double blind placebo-controlled Phase I cell therapy clinical trial in sero-positive, new-onset RA patients (within 2 years of diagnosis) who have high disease activity despite an adequate trial of a methotrexate, a Disease Modifying Anti-Rheumatic Drug (DMARD). The trial will take place at CWRU with two clinical performanace sites [MetroHealth Medical Center (MHMC) and University Hospitals Case Medical Center]. Cell based therapy using mesenchymal stem cells (MSCs) holds great promise. MSCs appear to be pericytes, poised to sense and repair damage arising from exogenous or endogenous threats, i.e. the ?guardians of inflammation?. These cells home to sites of inflammation and/or injury and facilitate repair while selectively reducing inflammation. The driving hypothesis for this clinical trial is that MSCs will have therapeutic value in restoring immune tolerance. MSCs have potential to delay or abort onset of full blown RA by resetting the immune system, inducing immune tolerance and dampening the observed amplification of adaptive immune mechanisms that perpetuate joint inflammation. Multiple RA therapies are available but none specifically repair autoimmunity; rather most interfere with both autoimmunity and protective host immunity. Most affected require lifelong therapy, rendering RA patients susceptible to infection and malignancy beyond that which RA itself confers. This study will focus on the safety of IV delivery of adult, bone marrow-derived allogeneic MSCs collected from a normal donor and expanded ex vivo. Patients will be randomized to MSCs or placeo and treated with a single infusion of MSCs while remaining on concomitant methotrexate except in the interval immediately after MSC infusion (so as not to damage the infused MSCs). Three MSC dose-escalation levels and studies will be performed. The enrollment schedule of one subject per month is acceptable to regulatory agencies. Dose escalation rules and early stopping rules have been developed. Patient reported outcomes (legacy and PROMIS) will be collected. In addition, we have engaged the Center for Health Disparities at MHMC in conducting focus groups to understand what RA patients think about the potential and appropriate timing for MSCs as RA therapy. An IRB application has been submitted and an IND submission will be completed prior to review of this application. Presuming safety, this study will be followed by a Phase II randomized placebo-controlled trial adequately powered to detect primary clinical and translational endpoints validated in the Phase I investigation. While the primary endpoint for the Phase I proof of concept program is safety, this study will use sensitive approaches to detect MSC immunologic effects in new onset RA patients in whom 12 weeks of methotrexate therapy has resulted in incomplete response (DAS28-CRP ? 4.4 ). Immunologic measures to detect tolerance will include measuement of number and function of Tregs using a novel functional biomarker developed in the PI's laboratory. At study end, we should be able to demonstrate safety of infusing MSCs in RA, pick two dosages for a successor Phase II trial, and identify which biomarkers should be used that trial.